This program project proposal on Alzheimer's Disease (AD) contains a Core and three research proposals. The major aim of this proposal is to investigate pathogenetic mechanisms in AD. This study will investigate trace element neurotoxicity, the serotonin hypothesis in AD and defective microtubule assembly in AD. The Core will function to 1) acquire and evaluate tissue from clinically thoroughly studied patients with AD, other CNS degenerative diseases and normal controls, 2) act as a central coordinating unit for the research project and 3) provide administrative supervision for the project. Project #1 tests the hypothesis that there are neurotoxic trace elements or imbalances of elements in AD that play a role in the degenerative changes in the brain. This project will use a new state-of-the-art LAMMA 500 laser activated microprobe mass analyzer, electron microscope with integrated electron energy loss spectrometry, instrumental neutron activation analysis and atomic absorption spectroscopy to study trace elements at the bulk, cellular and ultrastructural level in multiple brain regions and extra-neural tissue in AD and normal controls and brains of other CNS degenerative diseases. Project #2 addresses the interrelationship between serotonin, acetylcholine and AD pathological alterations in the amygdala and other brain regions. Serotonin content, uptake synthesis oxidation and subtype binding, other monoamine activity and acetylcholine binding synthesis and degradation will be correlated with quantification of neuron number, and NFT and SP counts. Project #3 is aimed at defining the mechanism of defective brain microtubule assembly in AD. Preliminary results have shown that a soluble factor in the frontal lobe of the AD brain blocks or modifies the GTP binding site on B-tubulin. Studies using photoaffinity probes will be aimed at defining if this alteration is present in other region of the AD brain or other CNS degenerative disorders with cytoskeletal alterations. Other studies will isolate and characterize this blocking factor. The differences in the ATP phosphorylation profile in AD will be investigated, in addition to studies to determine if there are differences in cAMP and cGMP protein kinases in AD and control brains.